Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Effects of the Mediterranean Diet on Cardiovascular Outcomes—A Systematic Review and Meta-Analysis

  • Thaminda Liyanage,

    Affiliations The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia, Armadale Kelmscott Memorial Hospital, South Metropolitan Health Service, Armadale, WA, 6112, Australia

  • Toshiharu Ninomiya ,

    tninomiya@georgeinstitute.org.au

    Affiliation The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia

  • Amanda Wang,

    Affiliation The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia

  • Bruce Neal,

    Affiliation The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia

  • Min Jun,

    Affiliations The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia, Department of Medicine, Division of Nephrology, University of Calgary, Calgary, Alberta, Canada

  • Muh Geot Wong,

    Affiliations The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia, Armadale Kelmscott Memorial Hospital, South Metropolitan Health Service, Armadale, WA, 6112, Australia

  • Meg Jardine,

    Affiliations The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia, Concord Repatriation General Hospital, Hospital Road, Concord, Sydney, NSW, 2139, Australia

  • Graham S. Hillis,

    Affiliation The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia

  • Vlado Perkovic

    Affiliation The George Institute for Global Health, Sydney Medical School, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW, 2050, Australia

Effects of the Mediterranean Diet on Cardiovascular Outcomes—A Systematic Review and Meta-Analysis

  • Thaminda Liyanage, 
  • Toshiharu Ninomiya, 
  • Amanda Wang, 
  • Bruce Neal, 
  • Min Jun, 
  • Muh Geot Wong, 
  • Meg Jardine, 
  • Graham S. Hillis, 
  • Vlado Perkovic
PLOS
x

Abstract

Background

A Mediterranean dietary pattern is widely recommended for the prevention of chronic disease. We sought to define the most likely effects of the Mediterranean diet on vascular disease and mortality.

Methods

We searched MEDLINE, EMBASE and the Cochrane Central Register without language restriction for randomized controlled trials comparing Mediterranean to control diets. Data on study design, patient characteristics, interventions, follow-up duration, outcomes and adverse events were sought. Individual study relative risks (RR) were pooled to create summary estimates.

Results

Six studies with a total of 10950 participants were included. Effects on major vascular events (n = 477), death (n = 693) and vascular deaths (n = 315) were reported for 3, 5 and 4 studies respectively. For one large study (n = 1000) there were serious concerns about the integrity of the data. When data for all studies were combined there was evidence of protection against major vascular events (RR 0.63, 95% confidence interval 0.53–0.75), coronary events (0.65, 0.50–0.85), stroke (0.65, 0.48–0.88) and heart failure (0.30, 0.17–0.56) but not for all-cause mortality (1.00, 0.86–1.15) or cardiovascular mortality (0.90, 0.72–1.11). After the study of concern was excluded the benefit for vascular events (0.69, 0.55–0.86) and stroke (0.66, 0.48–0.92) persisted but apparently positive findings for coronary events (0.73, 0.51–1.05) and heart failure (0.25, 0.05–1.17) disappeared.

Conclusion

The Mediterranean diet may protect against vascular disease. However, both the quantity and quality of the available evidence is limited and highly variable. Results must be interpreted with caution.

Introduction

Cardiovascular disease (CVD) is a leading cause of mortality worldwide accounting for one quarter of the estimated 52 million deaths in 2010[1,2]. The burden of CVD varies between regions and a proportion of this variability may be due to different dietary patterns[1,3].

Populations in the Mediterranean region have been reported to experience lower morbidity and mortality rates from CVD compared with northern European populations[4], which has been attributed to their consumption of a Mediterranean diet high in fruits and vegetables, nuts and cereals, fish, olive oil, with moderate red wine consumption and minimal amounts of red meat and dairy products[57]. In addition, the Mediterranean diet has been associated with beneficial effects on CVD risk factors such as glycaemia, blood pressure and lipid levels[810]. Two recent systematic reviews have showed some beneficial effects of the Mediterranean diet on the metabolic syndrome and its constituents but neither have explored the effects on vascular events or mortality[11,12].

Although there are randomized controlled trials (RCTs) assessing the effect of the Mediterranean diet on the primary or secondary prevention of CVD[13,14] the largest of these trials recorded just a few hundred events. There is also concern that one of the key trials supporting the beneficial effects of the Mediterranean diet was seriously methodologically compromised[15]. There is, therefore, real uncertainty about the data underpinning the value of the Mediterranean diet to human health. We undertook this systematic review and meta-analysis to better define the effects of the Mediterranean diet on cardiovascular events and mortality.

Materials and Methods

Data sources and searches

We performed a systematic review of the literature according to the PRISMA statement for the conduct of meta-analyses of intervention studies (www.prisma-statement.org) (S1 File). Relevant studies were identified by searching the following data sources: MEDLINE via Ovid (from inception through February 2014), EMBASE (from inception through February 2014) and the Cochrane Library database (Cochrane Central Register of Controlled Trials; no date restriction), using relevant text words and medical subject headings (S2 File). The search was limited to randomised controlled trials (RCTs) without language restriction. Reference lists from identified trials and review articles were manually scanned to identify any other relevant studies. The clinicaltrials.gov website was also searched for RCTs that were registered as completed but not yet published.

Study selection

The literature search, data extraction and quality assessment were conducted independently by two authors using a standardised approach (TL and AW). All completed RCTs assessing the effects of a Mediterranean diet compared to any control diet involving adults, with follow up period longer than three months, that reported one or more of the relevant outcomes were eligible for inclusion. Although there is considerable variability, a diet with non-restricted fat intake and with at least two of the following seven components was defined as a Mediterranean style diet for the purposes of this review; 1) use of olive oil as the main cooking oil, 2) moderate red wine consumption, 3) high consumption of nuts and/or legumes, 4) high consumption of grains and cereals, 5) high consumption of fruits and vegetables, 6) high consumption of fish with low consumption of meat and meat products and 7) low to moderate consumption of milk and dairy products[16].

Data extraction and quality assessment

Published reports were obtained for each trial and standard information about each trial was extracted into a spreadsheet. The data sought included summary metrics for each trial about baseline patient characteristics (age, gender, history of diabetes, history of hypertension, mean systolic and diastolic blood pressure levels, lipid levels, smoking status, body mass index and history of cardiovascular disease), details of the dietary intervention, follow-up duration, outcome events and adverse events. Study quality was judged according to the Cochrane risk of bias assessment tool[17]. Any disagreement in extracted data was adjudicated by a third reviewer (VP).

Outcomes

We sought data on total cardiovascular events (stroke, myocardial infarction, cardiovascular mortality or a broadly comparable definition reported by the study), coronary events (fatal or non-fatal myocardial infarction, coronary revascularization), cerebrovascular events (fatal or non-fatal stroke), heart failure, total mortality, incidence of type 2 diabetes mellitus, end-stage kidney disease, adverse effects (all adverse effects and serious adverse effects) and quality of life.

Data synthesis and analysis

Individual study relative risks (RRs) and 95% confidence intervals (CIs) were calculated from event numbers extracted from each trial. In calculating RRs, the total number of patients randomized in each group was used as the denominator. If no events were reported in either treatment or control group of any trial, 0.5 was used as the numerator. For the three arm PREDIMED study[14], the olive oil supplement arm and the nuts supplement arm were jointly considered as the treatment group whereas in the four arm study by Burr et al[18] only the “fish and fruit” arm fulfilled the defined criteria for the Mediterranean diet and this was compared to the “sensible eating” arm. Primary summary estimates of RRs were obtained using a random fixed effects model. Given the small number of included trials, publication bias and percentage of variability across studies attributable to heterogeneity beyond chance were not assessed as these may be unreliable. A two-sided p-value less than 0.05 was considered statistically significant. All analyses were performed with STATA, version 9.2 (Stata, College Station, Texas).

Results

Search results and characteristics of included studies

The literature search yielded 4637 articles, of which 51 were reviewed in full text (Fig 1). Of these, six RCTs, involving a total of 10950 participants, met the inclusion criteria. Among these, 477 major cardiovascular events were reported from three trials[13,14,19] and 693 deaths from five trials[13,14,1820]. The remaining study assessed the effect on quality of life[21]. The majority of the excluded trials did not study the Mediterranean diet as defined in the protocol, studied only individual components of the Mediterranean diet, did not report relevant outcomes, were not original investigations or were duplicate reports (S3 File).

The trials had a sample size that ranged from 48 to 7447 participants (Table 1). Two studies were single-centre[13,20] and four were multi-centre[14,18,19,21]. All studies provided dietary advice to participants and two studies provided food supplements in addition to dietary advice[13,14]. The studies were conducted between March 1988 and December 2010. The mean age of the study participants ranged between 41 and 67 years. One study only enrolled men[18], one study only enrolled women[21] and four studies enrolled both men and women[13,14,19,20]. Primary prevention was the objective of three studies[14,20,21], secondary prevention was the goal of two studies[13,18] and the remaining study included patients with and without a prior history of cardiovascular disease[19].

thumbnail
Table 1. Characteristics of the studies included in the systematic review and meta-analysis.

https://doi.org/10.1371/journal.pone.0159252.t001

In regard to study quality (Table 2), four of the six studies concealed the randomized allocation sequence[13,14,19,20], no studies were double-blinded and blinded assessments of outcomes were made in only 3 studies[13,14,19]. For one study subsequent publications raised serious concerns about the integrity such that the veracity of results was significantly in doubt[15,19].

Effects of Mediterranean diet on vascular outcomes and death

Major cardiovascular events.

Effects of the Mediterranean diet were reported for this outcome by three trials[13,14,19] including 9052 participants and 477 events. The Mediterranean diet was associated with a 37% relative reduction in the risk of major cardiovascular events (RR 0·63, 95% CI: 0·53–0·75, p< 0·001) compared to control diet. Exclusion of the study with serious concerns about its integrity (n = 1000, 145 events) did not result in a change of overall direction of the effect (RR 0.69, 95% CI 0.55–0.86, p< 0.001) (Fig 2).

thumbnail
Fig 2. Forrest plot of the included studies showing relative risk of Mediterranean diet compared to control diet by various outcome measures (Fixed effects model analysis).

https://doi.org/10.1371/journal.pone.0159252.g002

Fatal outcomes.

Data on all-cause mortality were available from 5 trials[13,14,1820] including 10671 participants and 693 deaths, four of which also separately reported data for cardiovascular mortality (10623 participants and 315 deaths) [13,14,18,19]. The Mediterranean diet had no clear effect on all-cause mortality (RR 1·00, 95% CI: 0·86–1·15, p = 0·97) or cardiovascular mortality (RR: 0·90, 95% CI: 0·72–1·11, p = 0·32) compared to control (Fig 2). Excluding the trial by Singh et al. further widened the confidence intervals (Fig 2). Across the various subgroups of studies examined (S1 and S2 Figs), greater benefits were suggested in small, single centre studies with incomplete follow-up.

Cause-specific cardiovascular outcomes.

Three trials[13,14,19] reported 221 coronary events and 167 cerebrovascular events. Use of the Mediterranean diet was associated with a relative risk of 0·65 (95% CI 0.50–0·85) (Fig 2) for coronary events and 0·65 (95% CI 0·48–0·88) for cerebrovascular events. Only two studies[13,19] involving 1605 participants and reporting 56 events were available to provide an effect estimate for heart failure, showing a relative risk of 0·30 (95% CI: 0·17–0·56). Exclusion of the data from the trial by Singh et al resulted in null findings for all of the cause specific outcomes except cerebrovascular events which continued to remain significant (RR: 0·66, 95% CI: 0·48–0·92, p = 0·01) (Fig 2).

Effects on other outcomes and adverse events.

One study that enrolled 279 participants reported data on quality of life[21]. There was a significant improvement with Mediterranean diet as measured by the Problem Areas in Diabetes (PAID) [22] self-care summary score (p = 0·005) but no effect on any other domain of that score or the Medical Outcome Study (MOS -12) short form general health survey[23] (all p>0.05). No data were available on new onset type 2 diabetes mellitus, end-stage kidney disease or adverse events for any of the included studies.

Discussion

This systematic review and meta-analysis supports the beneficial effects of the Mediterranean diet on cardiovascular outcomes, although the quantity and quality of the available evidence is relatively limited and there is much greater uncertainty about the effects of the Mediterranean diet than is widely understood as a result. There are also no data about adverse outcomes reported by any study, creating difficulties in the understanding of the overall balance between the risks and benefits of the Mediterranean diet. While the completed trials suggest it is likely that the Mediterranean diet protects against certain types of vascular diseases the evidence base falls short of that required to make definitive conclusions or firm recommendations.

Underpinning the rationale for the large-scale outcome trials were the findings of a series of prospective cohort studies[57] and recent reviews of those studies that reported moderately decreased risks of all-cause mortality, cardiovascular mortality and the incidence of cardiovascular disease associated with a Mediterranean diet[24,25]. However, observational studies of the effects of diet on cardiovascular disease are highly prone to confounding and it is hard to infer causation from these types of studies. Also in support of protective effects are the data from smaller RCTs examining the effects of Mediterranean diet on intermediate metabolic outcomes. These trials show small to moderate beneficial effects for multiple determinants of vascular risk[2628]. A recent overview of these RCTs trials identified blood pressure falls of 2.4mmHg (1.2 to 3.5) systolic and 1.6mmHg (1.1 to 2.0) diastolic, an LDL reduction of 2.71 mg/dl (5.03 to 0.39), a reduction in serum triglycerides of 6.14mg/dl (1.93 to 10.35) and an elevation in HDL cholesterol of 1.17mg/dl (0.38 to 1.96)[12].

Despite these encouraging findings, neither the cohort studies nor the RCTs of intermediate outcomes show benefits of a magnitude congruent with the very large point estimates of effect on cardiovascular outcomes proposed by some of the individual trials included in our review. Furthermore, while several other potential mechanisms of benefit such as antioxidant or anti-inflammatory effects have been postulated for the Mediterranean diet[29,30], large trials of intervention strategies specially targeting these pathways have been universally negative[31]. This raises an important question about the plausibility of large beneficial effects of the Mediterranean diet and raises concern about the possible effects of random or systematic errors. In regard to the former, the total volume of data available is small and much less than might typically be available for comparable investigations of the effects of drugs on the same outcomes. In terms of possible systematic errors, the un-masked design of the studies is a substantial weakness inherent in the nature of the intervention and may have led to differential ascertainment and assignment of outcomes across randomised groups. The much greater estimated treatment effects on more subjective outcomes like coronary events, strokes and heart failure compared to the non-significant estimates of effect for the objective outcome of mortality reinforces this possibility.

This review benefits from its comprehensive, systematic approach and the broad range of clinically important endpoints considered (S4 File). It does, however, suffer from a number of limitations. We could not explore heterogeneity across the individual study results for key outcomes in detail and our analyses based upon limited published summary data are restricted in their capacity to investigate this. Heterogeneity seems a possibility not only due to the different nature of the interventions used across the trials but also due to a combination of factors such as differing outcome definitions and varied durations of follow-up. In addition, the fact that larger benefits were seen in smaller, single-centre studies with incomplete follow up raises the possibility of overestimation of benefits by these studies. The absence of any data about the risks of adverse events is also a significant short-coming. Another issue affecting the evidence base supporting the use of the Mediterranean is the concern about the integrity of the trial by Singh et al.[19]. Following a site visit organized by the Lancet to Dr. Singh’s research facility due to concerns raised by multiple parties, including then the editor of BMJ, it was concluded that it was not possible to be sure of the rigor for recording data and its handling. While unable to point to specific evidence to refute the study's results, they raised concerns about the quality of the data likely to be generated from a research facility that lacked access to the kind of highly qualified support staff necessary to conduct a clinical trial to sufficiently high international standards. These concerns have been extensively reported and it is clear that the conduct and reporting of the trial are so weak as to raise serious concerns about the trial results[15]. If the Mediterranean diet was seeking registration or reimbursement under any regulatory assessment scheme it seems very unlikely that the data provided by the Singh trial would be eligible to contribute. Accordingly the best current estimates of the effect of the Mediterranean diet on cardiovascular outcomes are those that exclude the data from that study.

Conclusion

The American Heart Association/American College of Cardiology[32], the European Society of Cardiology[33] and the National Heart Foundation of Australia (www.heartfoundation.org.au) are three societies that all recommend the Mediterranean diet to reduce cardiovascular risk. All are careful to base this advice on the observed favorable although modest effects of the Mediterranean diet on intermediate cardiovascular risk factors. Clearly, recommendations based upon definitive clinical outcomes would be far preferable, and are supported by the findings of this review, however the strength of conclusions should remain circumspect because of the weakness of the evidence base. It seems unlikely that clinicians and patients fully appreciate the limitations of the data and the extent of the uncertainty. This is an area that warrants another well-conducted, adequately powered trial able to precisely and reliably define the overall balance of benefits and risks associated with the Mediterranean diet.

Prior Presentations of Results

This work has been presented at the American College of Cardiology Annual Scientific Sessions in 2015 in abstract form. The abstract is available from the following link: http://content.onlinejacc.org/article.aspx?articleid=2198774

Supporting Information

S1 Fig. Subgroup analysis of five studies reporting all-cause mortality.

https://doi.org/10.1371/journal.pone.0159252.s001

(TIFF)

S2 Fig. Subgroup analysis of four studies reporting cardiovascular mortality.

https://doi.org/10.1371/journal.pone.0159252.s002

(TIFF)

S3 File. List of rejected articles after full text review.

https://doi.org/10.1371/journal.pone.0159252.s005

(RTF)

Author Contributions

Conceived and designed the experiments: TL TN AW M. Jun VP. Analyzed the data: TL TN AW M. Jun VP. Wrote the paper: TL TN BN M. Jun M. Jardine VP. Data interpretation and critical revision of manuscript: TL TN AW BN M. Jun MW M. Jardine GH VP.

References

  1. 1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095–2128. pmid:23245604
  2. 2. WHO (September, 2011) Cardiovascular Diseases, Fact Sheet Number 317.
  3. 3. Reddy KS, Yusuf S (1998) Emerging epidemic of cardiovascular disease in developing countries. Circulation 97: 596–601. pmid:9494031
  4. 4. Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. (1986) The diet and 15-year death rate in the seven countries study. Am J Epidemiol 124: 903–915. pmid:3776973
  5. 5. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D (2003) Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 348: 2599–2608. pmid:12826634
  6. 6. Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, et al. (2004) Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 292: 1433–1439. pmid:15383513
  7. 7. Buckland G, Gonzalez CA, Agudo A, Vilardell M, Berenguer A, Amiano P, et al. (2009) Adherence to the Mediterranean diet and risk of coronary heart disease in the Spanish EPIC Cohort Study. Am J Epidemiol 170: 1518–1529. pmid:19903723
  8. 8. Psaltopoulou T, Naska A, Orfanos P, Trichopoulos D, Mountokalakis T, Trichopoulou A (2004) Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr 80: 1012–1018. pmid:15447913
  9. 9. Martinez-Gonzalez MA, de la Fuente-Arrillaga C, Nunez-Cordoba JM, Basterra-Gortari FJ, Beunza JJ, Benito S, et al. (2008) Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ 336: 1348–1351. pmid:18511765
  10. 10. Rumawas ME, Meigs JB, Dwyer JT, McKeown NM, Jacques PF (2009) Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham Offspring Cohort. Am J Clin Nutr 90: 1608–1614. pmid:19828705
  11. 11. Buckland G, Bach A, Serra-Majem L (2008) Obesity and the Mediterranean diet: a systematic review of observational and intervention studies. Obes Rev 9: 582–593. pmid:18547378
  12. 12. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB (2011) The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 57: 1299–1313. pmid:21392646
  13. 13. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. (1994) Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343: 1454–1459. pmid:7911176
  14. 14. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. (2013) Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 368: 1279–1290. pmid:23432189
  15. 15. Horton R (2005) Expression of concern: Indo-Mediterranean Diet Heart Study. Lancet 366: 354–356. pmid:16054927
  16. 16. Willett WC, Sacks F, Trichopoulou A, Drescher G, Ferro-Luzzi A, Helsing E, et al. (1995) Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr 61: 1402S–1406S. pmid:7754995
  17. 17. Higgins J (2011) Cochrane Handbook for Systematic Reviews of Interventions.Version 5.1.0.
  18. 18. Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, et al. (2003) Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr 57: 193–200. pmid:12571649
  19. 19. Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. (2002) Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomised single-blind trial. Lancet 360: 1455–1461. pmid:12433513
  20. 20. Ng GW, Chan UM, Li PC, Wong WC (2011) Can a Mediterranean diet reduce the effects of lipodystrophy syndrome in people living with HIV? A pilot randomised controlled trial. Sex Health 8: 43–51. pmid:21371381
  21. 21. Toobert DJ, Glasgow RE, Strycker LA, Barrera M Jr., Radcliffe JL, Wander RC, et al. (2003) Biologic and quality-of-life outcomes from the Mediterranean Lifestyle Program: a randomized clinical trial. Diabetes Care 26: 2288–2293. pmid:12882850
  22. 22. Polonsky WH (2000) Understanding and assessing diabetes-specific quality of life. Diabetes Spectrum 13: 36–41.
  23. 23. Stewart AL, Hays RD, Ware JE Jr. (1988) The MOS short-form general health survey. Reliability and validity in a patient population. Med Care 26: 724–735. pmid:3393032
  24. 24. Sofi F, Abbate R, Gensini GF, Casini A (2010) Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 92: 1189–1196. pmid:20810976
  25. 25. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N (2013) Mediterranean diet, stroke, cognitive impairment, and depression: A meta-analysis. Ann Neurol 74: 580–591. pmid:23720230
  26. 26. Rees K, Hartley L, Flowers N, Clarke A, Hooper L, Thorogood M, et al. (2013) 'Mediterranean' dietary pattern for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 8: CD009825. pmid:23939686
  27. 27. Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I, Tuttle KR, Estruch R, et al. (2011) Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors. Am J Med 124: 841–851.e842. pmid:21854893
  28. 28. Grosso G, Mistretta A, Frigiola A, Gruttadauria S, Biondi A, Basile F, et al. (2014) Mediterranean diet and cardiovascular risk factors: a systematic review. Crit Rev Food Sci Nutr 54: 593–610. pmid:24261534
  29. 29. Detopoulou Paraskevi, Constantinos AD Smaragdi Antonopoulou (2013) Mediterranean diet in a new perspective: A Systematic review for its benefits regarding mortality and cardiovascular disease and potential protective mechanisms. Hellenic Journal of Nutrition & Dietetics Vol 4: 27–43.
  30. 30. Schwingshackl L, Hoffmann G (2014) Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis 24: 929–939. pmid:24787907
  31. 31. Myung SK, Ju W, Cho B, Oh SW, Park SM, Koo BK, et al. (2013) Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 346: f10. pmid:23335472
  32. 32. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, et al. (2014) 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63: 2960–2984. pmid:24239922
  33. 33. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. (2012) European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 33: 1635–1701. pmid:22555213